WO2016160299A1 - Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental applications - Google Patents
Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental applications Download PDFInfo
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- WO2016160299A1 WO2016160299A1 PCT/US2016/021686 US2016021686W WO2016160299A1 WO 2016160299 A1 WO2016160299 A1 WO 2016160299A1 US 2016021686 W US2016021686 W US 2016021686W WO 2016160299 A1 WO2016160299 A1 WO 2016160299A1
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- 0 CC(*)(*)OC(*)(*)c1c(*)c(*)c(C(*)=C)c(*)c1* Chemical compound CC(*)(*)OC(*)(*)c1c(*)c(*)c(C(*)=C)c(*)c1* 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
- A61K6/887—Compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
- A61K6/889—Polycarboxylate cements; Glass ionomer cements
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
- A61K6/887—Compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- C08L33/04—Homopolymers or copolymers of esters
- C08L33/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
- C08L33/08—Homopolymers or copolymers of acrylic acid esters
Definitions
- Some current dental restorative applications may include: 1 ) a bisphenol A glycidyl methacrylate/triethylene glycol dimethacrylate (Bis-GMA/TEG-DMA) (see Figure 1 ), and/or a urethane dimethacrylate-based polymer to provide a resin network, 2) reinforcing filler particles treated with coupling agents (containing hydrolyzable ester connecting groups) to bind the resin to the particles, and 3) bonding agents (also containing hydrolyzable ester connecting groups).
- These systems and their accompanying use instructions may not produce satisfactory durability and esthetics over time. In addition to a short average service life, these systems are subject to leaching of unreacted monomers, bisphenol A (BPA), and system degradation products.
- composition of matter includes one or more functionalized vinylbenzyl components of the formula
- R functional components covalently connected to one or more R functional components; the one or more R functional groups selected from a group including one or more hydroxyl methyl (- CHOH-) moieties and/or derivatives thereof, one or more ethoxy (-CH 2 -CH 2 -0-) moieties and/or derivatives thereof, and one or more benzene (C 6 H 6 ) and/or derivatives thereof; and ether links that connect the functionalized vinylbenzyl components and the R functional components.
- R functional groups selected from a group including one or more hydroxyl methyl (- CHOH-) moieties and/or derivatives thereof, one or more ethoxy (-CH 2 -CH 2 -0-) moieties and/or derivatives thereof, and one or more benzene (C 6 H 6 ) and/or derivatives thereof; and ether links that connect the functionalized vinylbenzyl components and the R functional components.
- composition of matter consisting of one monomer or a mixture of monomers that include one or more functionalized vinylbenzyloxy components of the formula
- the one or more R functional components are selected from a group consisting of one or more hydroxyl methyl (-CHOH-) moieties and/or derivatives thereof, one or more ethoxy (- CH 2 -CH 2 -O-) moieties and/or derivatives thereof, and one or more benzene (C 6 H 6 ) derivatives, wherein ether links connect the functionalized vinylbenzyl components and the R functional components.
- the functionalized vinylbenzyloxy and the R components may be linked through one or more moieties chosen from a group consisting of -CH 2 -, -CH 2 CH 2 -, -C 3 H 6 -, -C(i-propyl) 2 -, -C H 8 -, -OCH 2 -, - CH 2 CH 2 0-, -OC 3 H 6 -, -OC 4 H 8 -, -C(CN) 2 -, -(CHOH)-, -C(CCI 3 ) 2 -, -C(CBr 3 ) 2 -, and - C(CF 3 ) 2 - moieties.
- compositions of matter as above made by polymerizing the resin monomers using methods including free-radical polymerization, cationic polymerization, or anionic polymerization.
- compositions of matter may be dental materials that are used as restorative materials, laminate veneers, denture repairing materials, and sealants.
- compositions of matter are dental materials that are used as dental adhesives, resin reinforced cements, and resin bonding or ceramic restorations.
- Figure 1 illustrates bisphenol A glycidyl methacrylate/triethylene glycol dimethacrylate (Bis-GMA/TEG-DMA) compounds
- Figure 2 illustrates an example application as a dental composite restorative system in which hydrolyzable methacrylate based-components are replaced with BPA-free and hydrolytically stable vinylbenzyl ether based components;
- Figures 3A - 3G illustrate chemical structures/formulas of resin monomers
- Figures 4A - 4F outline example synthesis plans for the resin monomers shown in Figures 3B - 3G;
- Figure 5 illustrates and experimental process for evaluating the enzymatic degradation performance of the herein disclosed resin monomers
- Figure 6 illustrates degradation products produced by the interaction of current resin monomers and esterase enzymes
- Figure 7 illustrates the resistance of the TEG-DVBE monomer to esterase degradation
- Figures 8A and 8B illustrate, respectively, degradation profiles for Bis- GMA and TEG-DMA monomers at different incubation time with esterases
- Figure 9A and 9B illustrate, respectively, the degradation of Bis-GMA /TEG-DMA polymers and the degradation resistance of TEG-DVBE polymers in the presence of the esterase enzyme
- Figures 10A and 10B are HPLC profiles illustrating degradation of Bis- GMA/TEG-DMA polymers and the degradation resistance of TEG-DVBE polymers.
- Figure 1 illustrates current bisphenol A glycidyl methacrylate/triethylene glycol dimethacrylate (Bis-GMA/TEG-DMA) compounds that are used in a variety of applications.
- One such application is as a component of a dental composite restorative system for cavities.
- This current dental composite restorative system further includes: 1 ) reinforcing filler particles treated with coupling agents (containing hydrolyzable ester connecting groups) to bind the resin to the particles, and 2) dentin/enamel bonding agents (also containing hydrolyzable ester connecting groups).
- coupling agents containing hydrolyzable ester connecting groups
- dentin/enamel bonding agents also containing hydrolyzable ester connecting groups
- the herein disclosed resins replace hydrolyzable methacrylate-based resins with BPA-free and hydrolytically stable vinylbenzyl ether based resins.
- three co-polymerizable compounds erythritol divinylbenzyl ether (E-DVBE), triethyleneglycol divinylbenzyl ether (TEG-DVBE), and the reaction products of vinylbenzyl glycidyl ether with N-tolylglycine salts (NTG- VBGE) (see Figure 2 for examples of their structures) were synthesized, purified, and evaluated as substitutes for currently used Bis-GMA, TEG-DMA, and NTG-GMA (Glycine, N-2-hydroxy-3-(2-methyl-1 -oxo-2-propenyl)-oxypropyl-N-(4-methylphenyl), monosodium salt) [CAS No. 133736-31 -9], respectively.
- Figure 2 illustrates an example application of a dental composite restorative system that uses the herein disclosed example resins and resin monomers.
- the dental composite restorative system includes a reinforcing filler, a silane-coupling agent, a polymeric phase resin network, and a surface-active monomer; placed on a tooth material.
- [0024] 1 Include easy handling resin monomers.
- the E-DVBE and TEG-DVBE have two terminal double bonds, which can each readily copolymerize, and can be used in the polymeric phase resin network.
- the TEG-DVBE is used to adjust and control the viscosity of the monomers to obtain good handling properties of dental composite restorative systems.
- the NTG-VBGE incorporated in the form of the sodium, magnesium, or other salt, is the active ingredient in dentin and enamel bonding, serving as a surface-active comonomer.
- E-DVBE is an ambiphilic compound with two hydrophobic vinylbenzyl groups at its ends and a flexible hydrophilic center (two hydroxyl groups from meso-erythritol).
- the vicinal hydroxyl groups can more easily form clusters of hydrogen bonds with the readily accessible hydroxyl groups of other such monomers. Modeling suggests that such clustering increases monomer density relative to its polymer, which should contribute to reduced polymerization shrinkage.
- Figures 3A - 3G illustrate chemical structures/formulas of the example resin monomers disclosed herein.
- Figures 3A - 3G also show how different the herein disclosed resin systems are from Bis-GMA/TEG-DMA-based resin systems.
- Human saliva contains esterase that can hydrolyze ester-containing compounds.
- Figure 3A illustrates a general chemical structure/formula for the herein disclosed resin monomers.
- the resin monomers may include a vinylbenzyl ether group.
- the attached R and X groups are defined with respect to Figures 3B - 3G.
- Xi (as numbered in Figure 3B) may be -H, -CH 3 , or -C2H5, and -H is preferred.
- HEMA hydroxyethylmethacrylate
- X may be -H, -CH 3 , or -C 2 H 5 ;
- X 2 , X3, Xe; and/or X 7 may be -H, -CH 3 , -OCH3, -CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -OC 2 H 5 , -OC 3 H 7 , or -OC 4 H 9 ;
- X 4 and/or X 5 may be -H, -CH 3 , -OCH 3 , -CF 3 , -F, -CL, -Br, -CN, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -OC 2 H 5 , -OC 3 H 7 , or -OC 4 H 9 .
- the compound is eryth
- These compounds may be an acid or the corresponding salt thereof, including sodium, magnesium, calcium, and strontium.
- Xi may be -H, -CH 3 , or -C 2 H 5 ;
- X 2 , X3, Xe; and/or X 7 may be -CH 3 , -OCH 3 , -CF 3 , -F, - CI, -Br, -CN, -C2H5, -C 3 H 7 , -C 4 H 9 , -OC 2 H 5 , -OC 3 H 7 , or -OC 4 H 9 ;
- X 4 and or X 5 may be - H, -CH 3 , -OCH3, -CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 , -C3H7, -C 4 H 9 , -OC 2 H 5 , -OC3H7, or - OC 4 H 9 ;
- X 8 and/or X 9 may be -H, -OH, -
- resin monomers are surfactants; they may replace the surfactants (e.g., NTG-GMA), in current dental restorative composite systems; e.g., as a surface active monomer in the adhesive-bonding components for dental resin composites.
- surfactants e.g., NTG-GMA
- Compound NTG-VBE is an example when Xi to Xi 3 are -H, Xi 4 is -CH 3 , and Ri is nothing.
- the synthesis plan for NTG-VBGE is shown in Figure 4B.
- m 4 1 , 2, 3, or 4;
- Xi may be -H, -CH 3 , or -C 2 H 5 ;
- X 7 may be -CH 3 , -OCH 3 , -CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , - OC 2 H 5 , -OC 3 H 7 , or -OC 4 H 9 ;
- X 4 and/or X 5 may be -H, -CH 3 , -OCH 3 , -CF 3 , -F, -CI, -Br, -CN, -C
- m 5 1 , 2, 3, or 4;
- Xi may be -H, -CH 3 , or -C 2 H 5 ;
- X 7 may be -CH 3 , -OCH 3 , -CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 , -C 3 H 7 , - C 4 H 9 , -OC2H5, -OC3H7, or -OC 4 H 9 ;
- X 4 and/or X 5 may be -H, -CH 3 , -OCH3, -CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 ,
- the functional groups on X 9 to X12 for example, using -CF 3 instead of -CH 3 groups
- the hydrophilicity/hydrophobicity of the resin monomers may be modified to improve miscibility with other resin monomers and reduce water absorption in oral environments.
- Xi may be -H, -CH 3 , or -C2H5;
- X 2 , X 3 , X 6 ; and/or X 7 may be -CH 3 , -OCH 3 , -CF 3 , -F, -CI, -Br, -CN, - C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -OC2H5, -OC 3 H 7 , or -OC 4 H 9 ;
- X 4 and or X 5 may be -H, -CH 3 , - OCH 3 , -CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -OC 2 H 5 , -OC 3 H 7 , or -OC 4 H 9 ;
- R 2 , and/or R 3 may be nothing, -(CH 2 ) m6 " , or - (CH 2 CH 2 0) m7 " ; m 6 may be 1 , 2, 3, ... or 18; and m7 may be 1 , 2, 3, 4, or 5.
- the compound is 1 ,4-bis(1 , 1 , 1 ,3,3,3-hexafluoro-2-((4-vinylbenzyl)oxy)propan-2- yl)benzene (HF-DVBE) when X 9 , X10, Xn and Xi 2 are -CF 3 ; R 2 and R 3 are nothing; and all of the other X groups are -H.
- the synthesis plan for HF-DVBE is shown in Figure 4D.
- the compound is 4,4',4"-((((2-methylbenzene-1 ,3,5- triyl)tris(methylene))tris(oxy))tris(methylene))tris(vinylbenzene) (B-TVBE) when R 4 , R 5 , and R 6 are nothing; and all of the X groups are -H.
- the synthesis plan for B- TVBE is shown in Figure 4F.
- a composition may include one or more functionalized vinylbenzyl components of the formula shown in Figure 3A covalently connected to one or more R functional components.
- the one or more R functional may be groups selected from a group consisting of one or more hydroxyl methyl (-CHOH-) moieties and/or derivatives thereof, one or more ethoxy (-CH 2 -CH 2 -0-) moieties and/or derivatives thereof, and one or more benzene (C6H6) and/or derivatives thereof; and ether links that connect the functionalized vinylbenzyl components and the R functional components.
- the functionalized vinylbenzyloxy(s) and the R components(s) may be linked through one or more moieties chosen from a group consisting of alkyl (-CH 2 -, -CH 2 CH 2 -, -C3H6-, -C(i-propyl) 2 -, and -C 4 H 8 -); alkoxy (-OCH 2 - -CH 2 CH 2 0-, -OC 3 H 6 -, and -OC 4 H 8 -); -C(CN) 2 -; hydroxyl substituted alkyl (-(CHOH)-); and halide substituted alkyl (-C(CCI 3 ) 2 -, -C(CBr 3 ) 2 -, and -C(CF 3 ) 2 -).
- the symbol X may refer to a hydrogen atom.
- one or more hydrogen atoms on the vinylbenzyl components may be replaced with functional moieties (to accelerate or slow down the rate of polymerization).
- the functional moieties may be one or more compounds or elements chosen from a group consisting of: -CH 3 , -C 2 H 5 , -OCH 3 , - CF 3 , -F, -CI, -Br, -CN, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -OC 2 H 5 , -OC 3 H 7 , and -OC 4 H 9 .
- the R functional components may be one or multiple ethoxy (-CH 2 -CH 2 -0-) moieties and their derivatives.
- the ether links may be formed through reaction of halide(s) and alcohol(s) in the presence of a strong base, preferably sodium hydride.
- the R functional components contain hydroxyl methyl (-CHOH)- moieties
- the ether links are formed through reactions of the functionalized vinylbenzyl halides and the primary hydroxyl moieties of one of the compounds of the group consisting of glycerol, erythritol, xylitol, mannitol, and sorbitol, in the presence of a strong base, preferably sodium hydride, and wherein the secondary hydroxyl group(s) are protected by protection groups while the ether links are formed, and the protection groups are removed after the ether links are formed.
- a strong base preferably sodium hydride
- the R functional components contain hydroxyl methyl (-CHOH-) moieties and the ether links are formed through reactions of the functionalized vinylbenzyl halides and hydroxyl moieties of one of the compounds of the group consisting of glycerol, erythritol, xylitol, mannitol, and sorbitol, in the presence of a strong base, preferably sodium hydride, wherein the mole amount(s) of functionalized vinylbenzyl halides is adjusted to be within a range of the mole amount of primary hydroxyls and the mole amount of primary hydroxyls plus secondary hydroxyl moieties (-CHOH-).
- a strong base preferably sodium hydride
- the R functional components are selected from the group consisting of N-(2-hydroxypropyl)-N-(p-styryl)glycine, N-(2-hydroxypropyl)- N-(phenyl)glycine, N-(2-hydroxypropyl)-N-(p-tolyl)glycine, N-(2-hydroxypropyl)-N- (3,5-dimethylphenyl)glycine, and N-(2-hydroxypropyl)-N-(vinylbenzyl)glycine, wherein each may be acidic, anionic, or preferably as a salt of one or more members of the group consisting of sodium, magnesium, calcium and strontium.
- an ether link connects each of the functionalized vinylbenzyl groups with each of these R functional groups.
- the ether link preferably is formed from a reaction of funtionalized vinylbenzyl glycidyl ether with members of the group consisting of N(H)-(p-styryl)glycine, N(H)- (phenyl)glycine, N(H)-(p-tolyl)glycine, N(H)-(3,5-dimethylphenyl)glycine, and N(H)- (vinylbenzyl)glycine.
- Each may be anionic, or a salt of one or more members of the group consisting of sodium, magnesium, calcium and strontium.
- a composition of matter may consist of one monomer or a mixture of monomers defined in Figures 3A - 3G.
- the resin monomer(s) may be used with cyanoacrylate based, methacrylate based, or epoxy based monomers or polymers.
- Figures 4A - 4F outline of the synthesis plans for the example resin monomers of Figures 3B - 3G, respectively.
- commercially available materials purchased from Alfa Aesar, Sigma-Aldrich and TCI America, were used as received.
- 1 H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), m (multiplets), etc. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br).
- FTIR Fourier transform infrared spectroscopy analysis
- TLC Analytical thin- layer chromatography
- Example 1 Synthesis of the sodium salt of NTG-VBE.
- the sodium salt of N (p-tolyl) glycine (0.05256 mol) was mixed with 100 g of distilled water.
- the pH of the mixture was measured and adjusted to about 9 by adding a 1 N aqueous NaOH solution drop-wise.
- the mixture turned into a clear solution.
- a solution containing vinylbenzyl glycidyl ether (0.05256 mol) and 0.0020 g of 2,4,6-tri-te -butylphenol (as a stabilizer to prevent premature polymerization) in 100 mL methanol was added drop-wise.
- Example 2 Synthesis of 1 ,12-bis(4-vinylphenyl)-2,5,8,11- tetraoxadodecane. Tryethylene glycol (8.02 mL, 9.01 g, 60 mmol) in DMF (30 mL) was added dropwise to a stirred suspension of NaH (95%)(3.79 g, 150 mmol) in DMF (120 mL) at 0-4 °C under Ar 2 atmosphere over 30 minutes.
- Example 3 Synthesis of 1 ,4-bis(1 ,1 ,1 ,3,3,3-hexafluoro-2-((4- vinylbenzyl)oxy)propan-2-yl)benzene.
- 1 ,4-Bis(2-hydroxyhexafluoro- isopropyl)benzene (10 g, 24.4 mmol) was added to a stirred suspension of K 2 CO 3 (10.1 g, 73.2 mmol) in DMF (70 ml_) under Ar 2 atmosphere.
- Example 5 Synthesis of (2R,3R)-1 ,4-bis((4-vinylbenzyl)oxy)butane- 2,3-diol.
- (4R,5R)-2,2-dimethyl-4,5-bis(((4-vinylbenzyl)oxy) methyl)-1 ,3-dioxolane crude (Example 4) was added to a stirred suspension of Dowex® 50W2X (10g, ) in MeOH (200 mL) at room temperature. The reaction mixture was then stirred and refluxed at 70 °C for 18 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure.
- resins may be employed in composites and the corresponding adhesives with specific functions as described above.
- different combinations of the resin monomers may be incorporated into and polymerized to provide resin components of a dental composite restorative system such as that illustrated in Figure 2.
- the resins have enzymatically and hydrolytically stable ether connections (instead of hydrolyzable ester groups) that attach the polymerizable vinylbenzyl groups of monomers of both the composite and its adhesive-bonding components.
- An example instruction for the herein disclosed dental composite restorative systems calls for an etching, washing, and removal of a smear layer on tooth surfaces to be treated.
- the smear layer represents a structurally weak layer that contains not only disrupted and fragmented tooth structures, but also extrinsic salivary pellicle, components of biofilms, and cariogenic microorganisms. It also plugs dentinal tubular openings, thereby preventing penetration of the adhesion- promoting monomeric components.
- the vinylbenzyl ether groups readily homopolymerize and copolymerize with methacrylate groups and other polymerizable groups including vinyl groups.
- the polymerization of the vinylbenzyl compounds may be initiated using initiators that are currently used in the methacrylate systems, for example: photo-initiators for wavelength 400-540 nm or dual-cure initiators for both light and chemical initiation.
- An example of photo-initiator is the mixture of camphorquinone (CQ) and ethyl 4- /V,/V-dimethylaminobenzoate (4E) at concentrations of 0.2 wt% and 0.8 wt%, respectively, of the polymer matrix.
- the compounds also are polymerizable using cationic and anionic polymerization mechanisms.
- the herein disclosed resin composites may be used with or without fillers.
- the composite's reinforcing filler particles have shapes, sizes, and surface treatments that allow for a maximum filler/resin ratio by surface treatment with different coupling agents attached by covalent bonds, e.g., a combination of three types of silanes including vinylbenzyltrimethoxy silane containing polymerizable vinyl groups to provide covalent bonding and cross-linking with the monomeric phase, octyltrimethoxy silane for improved rheological properties and vinylbenzyldimethylammoniumpropyltrimethoxy silane chloride, to minimize clustering or bridging and also contribute to interphase cross-linking.
- silanes including vinylbenzyltrimethoxy silane containing polymerizable vinyl groups to provide covalent bonding and cross-linking with the monomeric phase, octyltrimethoxy silane for improved
- the degree of vinyl conversion was determined using FTI R reflectance microspectroscopy (FTIR-RM).
- FTIR-RM FTI R reflectance microspectroscopy
- the Nicolet ⁇ FT-IR microscope operated in reflectance mode and interfaced with a Nicolet 6700 FT-I R spectrophotometer was equipped with two liquid nitrogen-cooled mercury cadmium telluride detectors (MCT-A: 1 1 ,700 - 650 cm "1 and MCT-B: 1 1 ,700 - 400 cm "1 ), a video camera, and a computer-controlled x-y translation stage.
- Spectra were collected with 64 scans from 650 cm “1 to 4000 cm “1 at 8 cm “1 spectral resolution with a beam spot size of 90 ⁇ x 90 ⁇ .
- Ten spectra each of three disks (8 mm in diameter and 1 mm in thickness) of every combination of resins were obtained from the flat top and bottom of the disks. Each spot was manually focused before data collection.
- the reflectance spectra were proportioned against a background of a gold coated slide and transformed to absorbance spectra using the Kramers-Kronig transform algorithm for dispersion correction, which converts the reflectance spectra to absorbance-like spectra.
- the degree of vinyl conversion was calculated as the reduction in the vinyl peak (1634 cm “1 ) height using the phenyl absorbance peak (1610 cm “1 ) as an internal standard.
- the peak heights were determined using the ISys software (Spectral Dimensions, Olney, MD, USA).
- the DC was the average of 30 spectra of three disks of each sample.
- FIG. 5 illustrates an experimental process for evaluating the enzymatic degradation performance of the herein disclosed resin monomers. The evaluation process is based on the hypothesis that in an environment containing esterases or cariogenic bacteria, traditional Bis-GMA and TEG-DMA monomers are converted to degradation products while the herein disclosed TEG-DVBE does not degrade in the same environment.
- method 500 begins in block 505 by determining a suitable model for esterase activity. For example, cholesteral esterase (CE) activity may be quantified by the degradation of a substrate and as a result, the change in the optical density (OD) formed by the degradation.
- CE cholesteral esterase
- Pseudocholinesterase activity may be tested by the degradation of butyrylthiocholin iodide (BTC) and by measuring changes in OD at a wavelength of 405 nm. According to this observation an enzyme activity may be defined that is equivalent to the optical change per minute at 405 nm, pH 7.0 and 25°C. This definition allows comparison between previous degradations studies that used a similar definition of units and substrates.
- BTC butyrylthiocholin iodide
- Cholesterol ester activity may be tested by the degradation of four nitrophenyl-isomers; o- nitrophenylacetate (o-NPA), p- nitrophenylacetate (p-NPA), o- nitrophenylbutyrate (o-NPB) and p- nitrophenylbutyrate (p-NPB) by measuring changes in OD at a wavelength of 410 nm and defining the CE activity as the change of absorbance of 0.01 OD per minute at 410 nm at pH 7.0 and 25°C.
- the esterase activity of model enzymes is measured and in block 515, target molecules are determined for HPLC measurement.
- the method 500 continues in block 520 with HPLC calibrations.
- the monomers and polymers are prepared and in block 530 the monomers and polymers are incubated with the model enzymes.
- the degradation of current and the herein disclosed resins are compared.
- the inventors of the herein disclosed resin monomers performed the method 500 to compare degradation of TEG-DVBE and traditional resin monomers (Bis-GMA and TEG-DMA) caused by the presence of esterase enzymes.
- the degradation compounds were detected and quantified with HPLC. After 24 hours incubation with the enzymes, no degradation was found in new resin monomers.
- Both Bis-GMA and TEG-DMA were decomposed dramatically by enzymes.
- Also evaluated was the resistance of new polymers made of TEG-DVBE and traditional polymers made of a mixture of Bis-GMA and TEG-DMA in 1 : 1 mass ratio to esterase enzymes. After 16 days challenge with the enzymes, no degradation was found in new polymers.
- Enzyme preparation began with cholesterol esterase derived from Pseudomonas bacteria (CE, C9281 , Sigma, Saint Louis, MO, USA) and Pseudocholinesterase from horse serum (PCE, C4290, Sigma, Saint Louis, MO, USA), which were reconstituted at desired concentrations in phosphate-buffered saline (D-PBS, 14190-144, Gibco®, Grant Island, NY, USA) and sterile filtered using a 0.22 ⁇ filter.
- D-PBS phosphate-buffered saline
- the prepared enzyme solutions used for replenishing enzyme activity in the biodegradation experiments were stored at -20 °C until needed.
- Enzyme activity assay (i.e., CE activity) was determined by para- nitrophenyl acetate (p-NPA) hydrolysis assay.
- P-NPA substrate (N8130, Sigma, Saint Louis, MO, USA) was prepared by dissolving p-NPA in methanol (100 mM p- NPA), and diluting with a 100 mM sodium acetate buffer, pH 5.0, to give a final p- NPA concentration of 1 mM.
- CE activity assay 50 ⁇ p-NPA solution, 50 ⁇ of CE solution (1 unit/mL) and 100 ⁇ sodium phosphate buffer (50 mM), pH 8.8, were added to a 96-well plate to give a final pH of 7.0, and the change of absorbance over time was measured at 410 nm at 25°C using a SpectraMax Microplate reader (Molecular Devices, Sunnyvale, CA, USA).
- One unit of CE activity is defined as a change of absorbance of 0.01 per minute.
- CE enzyme inhibition was assessed with the addition of 4 ⁇ of phenylmethanesulfonylfluoride (PMSF, 50 mM in anhydrous ethanol).
- PCE (1 unit/mL) activity was determined with acetylcholinesterase activity assay kit (MAK1 19, Sigma, Saint Louis, MO, USA) by measuring a change in absorbance at 412 nm, using butylthiocholine (BTC) as a substrate.
- One unit of PCE activity was defined as the formation of 1 .0 ⁇ of butyrate released per 1 mL of enzyme per minute at pH 7.5 and 25°C.
- the composition of conventional resin was 50:50 wt% Bis-GMA:TEG-DMA (Esstech, Essington, PA, USA) with 0.2 wt% Camphorquinone (CQ, 124893, Aldrich, Saint Louis, MO, USA) and 0.8 wt% ethyl 4- (diamethylamino)benzoate (DMAEMA, E24905, Aldrich, Saint Louis, MO, USA as the photoinitiator system.
- TEG-DVBE was mixed with 1 wt% II RGACURE 819 (1-819) and 1 wt% bis(4-tert-butylphenyl)iodonium hexafluorophosphate (DPI) as a photoinitiation system.
- Photoinitiation systems for each composition were selected to achieve resins with high degree of conversion.
- Monomer samples were filled into a 3 mm radius 1 mm height cylindrical Teflon mold, and between two Mylar films at the top and the bottom to prevent oxygen-inhibition of the surface layer. Additionally, glass slides were used in order to flatten the surface. The samples were photocured with a Triad 2000 visible light curing unit (Dentsply Trubyte, York, PA, USA) for 1 minute on each side.
- the hardened pellets with a 75 mm2 surface area were post- cured overnight in a vacuum oven at 60 °C, then incubated in D-PBS at 37 °C with stirring for 24 hours to remove any unreacted monomers. Pellets were then rinsed with distilled water and vacuum dried until they reach a constant mass.
- the incubation media was replaced every 48 hrs to maintain nominal enzyme activity. Each pooled media was quenched with the addition of 400 ⁇ _ methanol.
- the media from 2, 8, and 16 days of incubation periods were pooled for HPLC analysis. Pooled were centrifuged at 16000 rcf for 30 minutes and stored at 4°C until analysis with HPLC. Samples were also centrifuged for 30 minutes to eliminate large particles and stored at 4°C until analysis with HPLC.
- an Agilent 1290 Infinity Binary HPLC System was used for the chromatographic separation and quantification of the degradation products. Specifically, the disappearance of TEG-DMA, Bis-GMA and TEG-DVBE monomers, as well as the appearance of methacrylic acid (MA, 155721 , Aldrich, St. Louis, MO, USA) derived from TEG-DMA and Bis-GMA and bishydroxy propoxy phenyl propane (bis-HPPP, 15137, Fluka, Saint Louis, MO, USA) from Bis-GMA as degradation products where of interest.
- MA methacrylic acid
- Bis-HPPP bishydroxy propoxy phenyl propane
- a Zorbex Extend 5 ⁇ C18 4.6 x 250 mm column (770450-902, Agilent Technology, Santa Clara, CA, USA) was used for the separation of products.
- the mobile phase consisted of 2 mM buffer solution of HPLC-grade ammonium acetate (AX1222, EMD Chemicals Inc., Billerica, MA, USA) with pH adjusted to 3.0 with 6.0 N hydrochloric acid (A144-500, Fisher Scientific, Fair Lawn, NJ, USA) and HPL- grade methanol (MX0475, EMD Chemicals Inc., Billerica, MA, USA).
- the separation was achieved with 50% to 100% methanol in ammonium acetate buffer gradient for 30 minutes in order to provide comparison with reported tests results for current monomers.
- FIG. 7 HPLC profiles illustrate the resistance of the TEG-DVBE monomer to esterase degradation.
- Figure 7 is a chromatogram of the TEG-DVBE monomer exposed to an environment of the enzymes CE and PCE and the solvent D-PBS, and shows absorbance of these molecules versus time. As can be seen, no degradation products were found in any of the conditions.
- Figures 8A and 8B illustrate, respectively, degradation profiles for Bis- GMA and TEG-DMA monomers up to 24 hours.
- Figure 8A illustrates the degradation of the Bis-GMA monomer in the presence of the CE enzyme.
- the first plot illustrates absorbance of MA.
- the second plot illustrates absorbance of Bis- HPPP.
- the third plot illustrates absorbance of Bis-GMA.
- Figure 8B illustrates the degradation of TEG-DMA in the presence of the PCE enzyme up to 24 hour.
- the first plot illustrates absorbance of MA and the second plot illustrates the absorbance of TEG-DMA.
- Figure 9A and 9B illustrate, respectively, the degradation of Bis-GDMA and TEG-DMA monomers and the degradation of TEG-DVBE monomers in the presence of the esterase enzyme. Both figures plot incubation time (in days) versus cumulative absorption of MA in the presence of CE, PCE, and D-PBS. As can be seen, the Bis-GMA and TEG-DMA monomers show significant accumulation of MA while (in Figure 9B), TEGVBE shows negligible accumulation of MA.
- Figures 10A and 10B are chromatograms illustrating degradation of Bis- GDMA and TEG-DMA monomers and the TEG-DVBE monomer.
Abstract
Description
Claims
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EP16773707.1A EP3270870A4 (en) | 2015-03-17 | 2016-03-10 | Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental applications |
CA2978323A CA2978323A1 (en) | 2014-03-17 | 2016-03-10 | Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental applications |
KR1020177029765A KR20170129826A (en) | 2014-03-17 | 2016-03-10 | Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental applications |
JP2017548406A JP2018508541A (en) | 2015-03-17 | 2016-03-10 | Enzymatic and hydrolytically stable resins, resin monomers, and resin composites for dental applications |
AU2016244039A AU2016244039B2 (en) | 2014-03-17 | 2016-03-10 | Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental applications |
BR112017019946-7A BR112017019946B1 (en) | 2015-03-17 | 2016-03-10 | MATERIAL COMPOSITION UNDERSTANDING FUNCTIONED VINYLBENZILE COMPONENTS |
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US14/660,466 US9572753B2 (en) | 2014-03-17 | 2015-03-17 | Enzymatically and hydrolytically stable resins, resin monomers, and resin composites for use in dental preventive and restorative applications |
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EP (1) | EP3270870A4 (en) |
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US10690946B2 (en) * | 2015-08-26 | 2020-06-23 | Apple Inc. | Flexible photonic crystals with color-changing strain response |
US10246540B2 (en) * | 2015-09-29 | 2019-04-02 | Ada Foundation | Rapid azeotropic photo-copolymerization of styrene and methacrylate derivatives and uses thereof |
US10819441B2 (en) * | 2018-07-19 | 2020-10-27 | Nokia Solutions And Networks Oy | Adaptive digital filtering in an optical receiver |
US11309959B2 (en) | 2020-06-02 | 2022-04-19 | Nokia Solutions And Networks Oy | Direct-detection optical receiver capable of signal-to-signal beat interference cancellation |
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US20200297587A1 (en) | 2020-09-24 |
JP2018508541A (en) | 2018-03-29 |
BR112017019946A2 (en) | 2018-06-12 |
US20170049666A1 (en) | 2017-02-23 |
CA2978323A1 (en) | 2016-10-06 |
AU2016244039B2 (en) | 2021-08-12 |
US10675224B2 (en) | 2020-06-09 |
US9572753B2 (en) | 2017-02-21 |
US10231906B2 (en) | 2019-03-19 |
US10966909B2 (en) | 2021-04-06 |
KR20170129826A (en) | 2017-11-27 |
EP3270870A4 (en) | 2018-12-12 |
US20150257986A1 (en) | 2015-09-17 |
BR112017019946B1 (en) | 2021-04-06 |
US20190209438A1 (en) | 2019-07-11 |
EP3270870A1 (en) | 2018-01-24 |
AU2016244039A1 (en) | 2017-09-14 |
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